Osteocytes detect the need for mechanical adaptation and microdamage repair and signal to osteoblasts or[unreadable] osteoclasts, leading to bone gain or loss. Although long-lived, osteocytes undergo apoptosis, and their viability[unreadable] contributes to bone strength by mechanisms dependent and independent of changes in bone mineral density.[unreadable] During the preceding funding period, it was found that, similar to hormonal and pharmacological stimuli,[unreadable] mechanical forces regulate osteocyte lifespan. Thus, mechanical stimulation in vitro prevents osteocyte apoptosis[unreadable] via an integrin/Src/ERK pathway that requires the integrity of caveolae and a ligand-independent function of the[unreadable] estrogen receptor (ER). Conversely, reduced mechanical forces in vivo increase osteocyte apoptosis, and this[unreadable] event temporally precedes, and is spatially associated with, osteoclast-mediated resorption and the subsequent[unreadable] loss of mineral and strength. It was also found that during aging bone strength decreases before a reduction in[unreadable] bone mineral density, and osteocyte apoptosis increases. Based on this knowledge, it is proposed that[unreadable] mechanical stimuli trigger ERK-dependent signals that sustain osteocyte survival via a signalsome assembled in[unreadable] caveolae and composed of integrins and signaling molecules, including the ERs. Conversely, diminished[unreadable] mechanical forces?from reduced physical activity with age?eliminate the signals that maintain osteocyte[unreadable] viability, thereby leading to apoptosis. Dying osteocytes in turn recruit osteoclasts to the vicinity. Both[unreadable] mechanisms, disruption of the integrity of the osteocyte network and increased osteoclastic bone resorption,[unreadable] contribute to the age-related decline in bone strength and mass. To validate these hypotheses, in Aim 1 will be[unreadable] defined in vitro the role of the ER and caveolin-1 in ERK-mediated anti-apoptosis induced by mechanical[unreadable] stimulation; and whether other survival signaling pathways act in concert to control osteocyte death. In Aim 2, it[unreadable] will be determined in vivo whether mechanically induced survival signaling is disrupted by unloading and during[unreadable] aging, and established whether unloading- or aging-induced osteoclast-mediated resorption and loss of bone and[unreadable] strength are ameliorated by inhibiting osteocyte apoptosis by 1) constitutively activating the ERK pathway in OG2-[unreadable] MEK-SP mice, 2) overexpressing the anti-apoptotic protein Bcl-2 in DMP1-Bcl2 mice, and 3) treating with a[unreadable] unique bisphosphonate that inhibits osteocyte apoptosis without affecting osteoclasts. In Aim 3, it will be[unreadable] established whether induction of osteocyte apoptosis is sufficient to trigger osteoclast recruitment and whether[unreadable] the kinetics of the osteoclastogenic response to osteocyte apoptosis are altered with aging. These studies will[unreadable] advance our understanding of the mechanistic basis for the profound role of mechanical forces, or lack of thereof,[unreadable] in skeletal health and disease, and will establish the contribution of osteocyte apoptosis to the loss of bone[unreadable] strength that ensues with aging. We expect that this work will provide new avenues for the treatment of bone[unreadable] fragility in conditions of reduced physical activity, such as in the elderly or during the temporary immobilization of[unreadable] bed rest, space flight, and motor paralysis.